Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care

Vascular Malformations Clinical Trial

Official title:

Phase III Multicentric Study Evaluating the Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02638389
• Other study ID #: VASE
• Status: Recruiting
• Phase: Phase 3
• Start date: January 25, 2016
• Est. completion date: April 1, 2030

Study information

• Verified date: February 2023
• Source: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Contact: Laurence M. Boon, MD, PhD
• Phone: + 32-2-764 8020
• Email: laurence.boon[@]uclouvain.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The phosphatidylinositol 3-kinase (PI3Kinase)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTor) pathway plays a role on the development and the venous/lymphatic vascular organisations.

The investigators want to study the efficacy and the safety of Rapamycin, an mTor inhibitor.

Description:

The complex vascular malformations induce chronical pains and organic dysfunctions causing significant morbidity and mortality. Therefore, the investigators need to establish guidelines in order to treat these pathologies. Standard treatments such as surgery or interventional radiology are of limited efficacy and related to a high level of recurrences as well as complications. Recent preclinical studies have shown the important role of the PI3Kinase/AKT/mTor pathway on the development and the venous/lymphatic vascular organisations suggesting an appealing therapeutic target to treat patients with venous, lympathic or complex vascular malformations.

Investigators will realize a multicentric phase III study enrolling a higher number of patients to statistically evaluate the efficacy and the safety of the Rapamycin, an mTOR inhibitor, in the treatment of children and adults with vascular malformations for which conventional therapies such as surgery or sclerotherapy are ineffective or associated with high risk of important complications. Nearly 250 patients (200 adults and 50 children) will be enrolled in several european centers.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: April 1, 2030
• Est. primary completion date: April 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 70 Years

Eligibility

Inclusion Criteria:

• Patients with complex vascular anomalies that are refractory to standard care such as medical treatment, surgical resection and/or sclerotherapy/embolization (ineffective or accompanied by major complications)

• Patients must have adequate medullary function: Hemoglobine> 10,0 g/dl, neutrophils >1500/mm³ and platelets > 100.000/mm³

• Patients must have the following laboratory values:

• Total serum bilirubin = 1.5 x ULN (or totally bilirubin = 3 x ULN with direct bilirubin = 1.5 x ULN in patients with well documented Gilbert Syndrome)

• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3 x ULN (or < 5.0 x ULN if hepatic metastases are present)

• Serum creatinine 1.5 x ULN. If the serum creatinine is = 1.5 x ULN, then a 24-hour Creatinine Clearance must be conducted and the result must be = 60 mL/min.

• Karnofsky > 50

• Patients have to be able to sign the informed consent

• Women in age of procreation have to be informed that contraceptive methods are mandatory during the study time

Exclusion Criteria:

• Any of the following concurrent severe and/or uncontrolled medical conditions, which could compromise participation in the study or interfere with the study results:

• Impaired cardiac function or clinically significant cardiac diseases, including unstable angina pectoris, ventricular arrhythmia, valvular disease with documented compromise in cardiac function, myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function, history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy, family history of congenital long or short QT, or known history of QT/QTc prolongation of Torsades de Pointes (TdP)

• Impairment of Gastro-Intestinal (GI) function or GI disease that may significantly alter the absorption of sirolimus (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea = Grade 2, malabsorption syndrome, or small bowel resection)

• Known hypersensitivity to drugs or metabolites from similar classes as study treatment.

• Patient has other concurrent severe and /or uncontrolled medical condition that would,in the investigator's judgment, contraindicated participation in the clinical study (e.g. acute or chronic pancreatitis, liver cirrhosis, active chronic hepatitis, severely impaired lung function with a spirometry = 50% of the normal predicted value and/or O2 saturation = 88% at rest, etc.)

• Immunocompromised patients, including known seropositivity for HIV

• Pregnant or lactating women

• Prior treatment with PI3K and/or mTOR inhibitors

Related Conditions & MeSH terms

• Vascular Malformations

Intervention

Drug:
• Sirolimus
evaluate the efficacy and safety of sirolimus in these patients

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Bruxelles	Bruxelles	Région De Bruxelles-Capitale
France	CHU Caen	Caen	Bretagne
Germany	Universitätsklinikum Freiburg	Freiburg

Sponsors (1)

Lead Sponsor	Collaborator
Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Countries where clinical trial is conducted

Belgium,  France,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Self-assesment (or parent assesment), using visual anagogic scale (0-10) of efficacy of sirolimus	Global treatment efficacy; Pain; Local complications/symptoms (bleeding, skin tension, esthetic and functional impairment)	every 3 months, up to 2-year period.
Secondary	Number of enrolled patients with treatment-related adverse events as assessed by CTCAE v4.0		every month during the first three months and then every three months for a 2-year-treatment period
Secondary	Self assessment of quality of life change induced by sirolimus	Measured by quality of life questionnaire (adapted to MOS SF-36 survey).	every 3 months, up to 2-year period.
Secondary	Volumetric changes of the malformation on sirolimus, based on magnetic resonance imaging (MRI) 12 months after sirolimus onset.	Relative change of volume of the vascular malformation between the baseline MRI (before sirolimus onset) and the 12-month MRI (during sirolimus treatment)	At 12 month
Secondary	Efficacy of sirolimus	Change in plasma levels fibrinogen and/ or D-dimers, reflecting improvement in an abnormal intravascular coagulation consumption	every three months, up to 2-year period
Secondary	Efficacy of sirolimus measured on digital photographs	Qualitative assessment of efficacy on digital photographs	every three months, up to 2-year period